AIDS-related lymphomas (ARL) are a group of immune deficiency-associated, aggressive B cell, non-Hodgkin's lymphomas (NHL-B). The incidence of ARL in the US is currently increasing, as AIDS patients live longer, and become at greater risk for the later consequences of immune compromise. The biology of ARL, that primarily results in the small non-cleaved cell (SNCC; Burkitt's (BL)) or Large cell (Immunoblastic) histo-types, seems to involve a number of the pathogenetic programs involved in aggressive NHL-B in the HIV negative patient population, However, the rapidity of development and the prodigious cell growth potential of ARL, suggests that additional genetic, biologic, or immune factors may be involved. The biologic or molecular basis of the aggressive malignant B cell growth in the ARL is unknown. ARL arises in the B lymphoid cell lineage, after the accumulation of a variable number of specific oncogene, viral, or tumor suppressor gene abnormalities that lead to cellular immortalization in NHL-B precursor cells. Studies will pursue our preliminary results that suggest that the immortalized, NHL precursor B cells, aberrantly express one or more of the BCGF (IL14, LMW-BCGF) cytokine genes, probably as part of the malignant transformation process. inappropriately expressed BCGF genes in ARL become autocrine growth factors (AGF) for the lymphoma cells, that also constitutively express the IL-I4R. Co-stimulatory factors for normal B cell proliferation, such the CD4O ligand (CD4OL) gp39, will also be evaluated for growth stimulatory potential in the ARL. Other cytokines with putative B cell stimulatory activity, such as IL6 or lL1O, will also be studied for a possible role in mediating or co-stimulating ARL cell growth in vitro. Since autocrine growth in the ARL appears to be mediated by BCGF molecules, we will explore methods for inhibiting cell growth thru growth factor deprivation, by inhibiting these cytokine growth factor genes in the ARL, with cytokine inhibitory drugs, such as cyclosporin A (CsA), and anti-sense oligonucleotides (ASO). Pathogenesis of the ARL will be explored in vitro, in experimental B cell models, containing transfected oncogenes and growth factor genes, that will be extended to in vivo studies, utilizing immune deficient. SCID mice. Finally, we will seek to identify additional (or different) genetic lesions in the ARL, possibly accounting for the accelerated development and/or aggressive clinical behavior, using comparative genomic hybridization (CGH), for identifying chromosomal abnormalities, not identifiable using conventional cytogenetic techniques.